Continuous Flow Chemistry: Reaction of Diphenyldiazomethane with p-Nitrobenzoic Acid

The overall goal of this technique is to transfer chemical processes from batch to flow mode as demonstrated by the reaction of diphenyldiazomethane with para-Nitrobenzoic acid in a continuous flow reactor. This method can help identify how best to approach the technology transfer of chemical transformations from batch to flow processes. The main advantage of this techniques are chemical reactions that require precise temperature control and mixing or highly reactive intermediate or reagents.

It is essential to first establish reaction kinetics and operational parameters in batch mode. After reaction optimization, the process can be transferred to flow mode. First, check that each high-pressure 500 milliliter syringe pump is connected to its own pump controller.

Empty the solvent collection beakers. Place 400 milliliters of reagent grade ethanol in a clean beaker. Transfer one syringe pump inlet feed tube to the beaker and fully open the corresponding pump inlet valve.

Then, on the syringe pump controller, select Constant Flow in the port connecting the controller to the pump transducer. Start filling the syringe pump with ethanol at 70 milliliters per minute. Monitor the flow rate reading and the solvent level in the beaker.

Express the air from the pump. Once the syringe pump is full and pumping has stopped, close the inlet valve. Repeat this process to fill the second syringe pump with ethanol.

Then, open one pump outlet valve and start flowing ethanol through the continuous flow reactor system. Set the flow rate to 30 milliliters per minute. Check for leaks and blockages and verify that the ethanol is flowing through the entire reactor.

Once the pump is empty, close the outlet valve and repeat the process with the other syringe pump. Clean each pump in this way, two to three times. Then, close the valves and empty the solvent waste.

To begin the synthesis, place the inlet tube of the syringe pump connected to the second module in 100 milliliters of a 0.01 molar solution of DDM in anhydrous ethanol spiked with toluene. Open the pump inlet valve. Draw up the DDM solution at 70 milliliters per minute.

If some solution is left in the flask when the pump stops, transfer the pump outlet tube to the flask of DDM solution and open the outlet valve. Decrease the flow rate to 30 milliliters per minute and run the pump until the solution appears in the outlet tube. Then, stop the pump.

After drawing up the DDM solution, purge the syringe pump of air until the solution has been fully loaded into the pump. Then, close the outlet valve. Transfer the solution to a cuvette for UV-VIS spectroscopy.

Set the DDM pump flow rate to 1.42 milliliters per minute. Fill the other pump with 250 milliliters of a 0.1 molar solution of para-nitrobenzoic acid in anhydrous ethanol spiked with orthoxylene. Set that pump to 3.58 milliliters per minute.

Once both pumps have been filled, and their outlet valves are open, start the pumps. Monitor the flow into modules one and two and the mixing in modules three and four. The solution should be colorless after module four.

Collect aliquots at 90-second intervals and monitor the reaction with UV-VIS spectroscopy. Once the reaction is complete, clean the pumps twice each with 400 milliliters of ethanol. Flow through the system at 10 milliliters per minute.

Then, fill each pump with air and push the air through the system to finish cleaning. The reaction of at least a 10-fold excess of para-nitrobenzoic acid in DDM in a continuous flow reactor was monitored with UV-VIS spectroscopy. Comparison to a batch reaction performed with a 10 to one molar ratio, indicated the successful transfer of the procedure from batch to flow mode.

95%reaction completion was achieved within the 11 minute residence time of the continuous flow reaction. Complete conversion could be achieved by extending the residence time to 33 minutes. While attempting this procedure, remember to use appropriate and calibrated temperature, pressure and flow controls.

The reactor and pumps must be carefully cleaned before subsequent use for either the same or a different process. After watching this video, you should have a good understanding of how to perform a continuous flow reaction. Flow technology offers significant advantages over batch processing, including the capability to scale out an existing system to larger scales.

The ability to acquire data in tandem with flow processes is a powerful tool that can be expanded to many other fields of research. We hope this technique encourages scientists to adopt flow technology as a tool.